1. Field of the Invention
The present invention relates generally to the fields of chemical synthesis. More particularly, it concerns the synthesis of 3-aminomethyl-1-propanol, a Fluoxetine precursor.
2. Description of Related Art
Fluoxetine is a selective serotonin uptake inhibitor presently available for the treatment of depression under the trade name Prozac™. Its chemical name is typically N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propyl amine in much of the literature; its name for indexing in Chemical Abstracts is (±)-N-methyl-γ-[4-(trifluoromethyl)phenoxy] benzenepropanamine. Thus, improved processes for the commercial preparation of fluoxetine are of considerable value.
Numerous processes are known in the literature. The original U.S. Patents to fluoxetine (U.S. Pat. Nos. 4,314,081 and 4,194,009) describe syntheses beginning from 3-dimethylaminopropiophenone, which is reduced with diborane, chlorinated with thionyl chloride, condensed with 4-trifluoromethylphenol, and demethylated with cyanogen bromide and potassium hydroxide in ethylene glycol. This process was somewhat improved by Robertson et al. (1987) by condensing the alcohol with 4-chlorobenzotrifluoride and by replacing cyanogen bromide with phenylchloroformate.
European application 529842 discloses an improved process in which 3-dimethylamino-1-phenyl-1-propanol is reacted with an alkyl chloroformate and hydrolyzed to provide 3-methylamino-1-phenyl-1-propanol, which is then condensed with 4-chloro- or 4-fluorobenzotrifluoride. European application 457559 describes a chiral synthesis of the 3-dimethylamino-1-phenyl-1-propanol that is used as a starting material in the foregoing European application. The chiral synthesis is accomplished by reduction of the corresponding ketone with lithium aluminum hydride using (2R,3S)-(−)4-dimethylamino-1,2,-diphenyl-3-methyl-2-butanol as a chiral ligand. A similar chiral reduction has been described by Sakuraba et al. (1991) using a different chiral reducing agent. Another approach, described in European patent 380924, proceeds by reduction of ethylbenzoylacetate and subsequent aminolysis of the ethyl ester with methylamine. The reduction of ethylbenzoylacetate can also be accomplished in an enantioselective manner using baker's yeast (Kumar et al., 1992). A ruthenium catalyst having a chiral ligand has been employed in a similar catalytic reduction by Ager and Laneman, (1997).
One of the key intermediates of fluoxetine synthesis is 3-(methylamino)-1-phenyl-1-propanol (Formula 1). There are three general approaches to the synthesis of this aminoalcohol. The first method is based on the reduction of the carbonyl group of 3-substituted propiophenones (halo, dialkylamino, amido, carboethoxy) followed by the conversion of the above functionalities into the methylamino group (U.S. Pat. Nos. 4,902,710 and 5,936,124; Finnish Patent FI 81083; European Application EP 529842; Spanish Patents, ES 2101650 and ES 2103681; International Application WO 0037425; Foster et al., 1990; Kairisalo et al., 1990; Schwartz et al., 1993; Pedregal, 1997; Arce, 1997; Weber and Marti, 2000; Robertson et al., 1988; Corey and Reichard, 1989; Kumar et al., 1991; Chenevert, 1991; Sakuraba, 1995; and Hilborn et al., 1999). In the second approach, phenylisoxazolidine is synthesized first, and then transformed into 3-(methylamino)-1-phenyl-1-propanol by reductive ring cleavage (U.S. Pat. No. 5,760,243; Int. Appl. WO 9906362; Theriot, 1998; Theriot, 1999; and Wirth et al., 2000). The third general method is based on the ring opening of epoxystyrene or its derivatives followed by the conversion of 3-functionally substituted 1-phenylpropanols into 3-(methylamino)-1-phenyl-1-propanol (U.S. Pat. No. 5,104,899; PCT Int. Appl. WO 9309769; Gao and Sharpless, 1988; Young and Barberich, 1993; Young and Barberich, 1992; and Mitchell and Koenig, 1995). Although the majority of the reported syntheses of 3-(methylamino)-1-phenyl-1-propanol are simple and efficient, some of them require two reduction steps, which lowers overall yields.